Antiplatelet in ACS

1. Antiplatelet Therapy in ACS
MASRUL SYAFRI, MD, PhD
MAT-ID-2101140-v1.0 (09/2021)

2. Mechanism Antithrombotic Therapy
Rodriguez F, Harrington RA. N Engl J Med. 2021;384(5):452-460.

3. Management of Antithrombotic Therapy
after Acute Coronary Syndromes
ACS, acute coronary syndrome; DOAC, direct oral anticoagulant; mo, month(s).
Rodriguez F, Harrington RA. N Engl J Med. 2021;384(5):452-460.

4. DAPT choice for elder patients?
 TRITON-TIMI 38 trial and PLATO trial showed superiority of prasugrel and ticagrelor
versus clopidogrel in reducing cardiovascular death, MI, and stroke.
 With increasing age, patients have higher risks of bleeding and thrombotic events.
 TRITON-TIMI 38 did not show a net clinical benefit of prasugrel in the subgroup of
older patients (aged ≥75 years), due to higher rates of bleeding.
 In the PLATO trial, ticagrelor related bleeding occurred more frequently than did clopidogrel related bleeding,
especially in older patients.
Rationale
Objective
 To determine the optimal P2Y12 inhibitor in older patients with NSTE-ACS by
assessing the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel
in patients aged 70 years or older.
MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute
coronary syndrome.
Gimbel M, et al. Lancet. 2020;395(10233):1374-81.

5. Study design and methods
N = 1011
Within 72 hours after admission
Clopidogrel 75mg QD
(n = 506)
Ticagrelor 90 mg BID or
Prasugrel 10 mg QD
(n = 505)
Clopidogrel 75mg QD
(n = 500)
Ticagrelor 90 mg BID or
Prasugrel 10 mg QD
(n = 502)
Randomization 1:1
3 dropped out
6 dropped out
Endpoints assessment
ITT analysis
Treatment for 12 months
An open-label, randomized trial targeting patients aged 70 years or older, presenting with a NSTE-ACS
Gimbel M, et al. Lancet. 2020;395(10233):1374-81.
BID, twice daily; QD, once daily; ITT, intention to treat; NSTE-
ACS, non-ST-elevation acute coronary syndrome.

6. Study endpoints
Presentation title | XX Month XXX BARC, bleeding academic research consortium; PLATO, platelet inhibition and patient outcomes; TIMI,
thrombolysis in myocardial infarction.
Bleeding outcomes
PLATO bleeding
TIMI bleeding
BARC bleeding
Thrombotic outcomes
All-cause death
Myocardial infarction
Stroke
Cardiovascular death
Ischemic stroke
Unstable angina
Transient ischemic attack
Stent thrombosis
Urgent revascularization
Primary endpoint
• Bleeding outcome:
PLATO bleeding* major & minor
• Net clinical benefit outcome:
composed of all-cause death, myocardial infarction†,
stroke‡ and PLATO major or minor bleeding
Secondary endpoint
• All thrombotic outcomes
• All bleeding outcomes
* Defined according to the criteria of the PLATO trial
† Defined according to the third universal definition of myocardial infarction
‡ Defined as an acute new neurological deficit ending in death or lasting >24 h not due to
another readily identifiable cause such as trauma
Gimbel M, et al. Lancet. 2020;395(10233):1374-81.

7. Baseline Characteristics
Gimbel M, et al. Lancet. 2020;395(10233):1374-81.
• The baseline characteristics were
well balanced between both
treatment groups

8. Results
CI, confidence interval; HR, hazard ratio. Gimbel M, et al. Lancet. 2020;395(10233):1374-81.

9. Conclusions
MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome.
Gimbel M, et al. Lancet. 2020;395(10233):1374-81.

10. PHILO (TW/JP/KR): Trial Design
• Design: Multicenter, double-blind, randomized trial
• Patient type: Patients with ACS, and all were planned to undergo PCI and randomized within 24
h of symptom onset
• Ethnicity: 801 East Asians (Japanese, n = 721; Taiwanese, n = 35; South Korean, n = 44; unknown
ethnicity, n = 1)
ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; bid: twice daily; qd: once daily
Concomitant Aspirin 75-100 mg
Goto S, et al. Circ J. 2015;79(11):2452-2460.
Group Patient no. Loading dose Maintenance dose
Ticagrelor 401 180 mg 90 mg bid
Clopidogrel 400 300 mg 75 mg qd

11. PHILO : Efficacy Results
• In ACS patients from Japan, Taiwan and South Korea, event rates of primary safety and efficacy endpoints were higher, albeit
not significantly, in ticagrelor-treated patients compared with clopidogrel-treated patients.
Data given as n (%). ACS, acute coronary syndrome; ATE, arterial thromboembolic event; CV,
cardiovascular; MI, myocardial infarction; RI, recurrent cardiac ischemia; SRI, serious recurrent
ischemia; TIA, transient ischemic attack.
Primary and Secondary Efficacy Endpoints
Ticagrelor
90 mg b.i.d. (n = 401)
Clopidogrel
75 mg o.d. (n = 400)
HR (95% CI)
Primary
Composite of CV death/MI (excluding silent MI)/stroke 36 (9.0) 25 (6.3) 1.47 (0.88 – 2.44)
Post-hoc
Composite of CV death/spontaneous MI/stroke 18 (4.5) 13 (3.3) 1.39 (0.68 – 2.85)
Secondary
Composite of all-cause mortality/MI (excluding silent MI)/stroke 37 (9.2) 25 (6.3) 1.51 (0.91 – 2.50)
Composite of CV death/total MI/stroke/RI (including SRI)/TIA/Other
ATE
38 (9.5) 32 (8.0) 1.20 (0.75 – 1.93)
MI (excluding silent MI) 24 (6.0) 15 (3.8) 1.63 (0.85 – 3.11)
Peri-procedure MI 18 12 -
Spontaneous MI 6 3 -
CV death 9 (2.2) 7 (1.8) 1.28 (0.48 – 3.45)
Stroke 9 (2.2) 6 (1.5) 1.50 (0.54 – 4.23)
All-cause mortality 10 (2.5) 7 (1.8) 1.42 (0.54 – 3.74)
Goto S, et al. Circ J. 2015;79(11):2452-2460.

12. PHILO (TW/JP/KR): Major Adverse Cardiovascular Event
CV, cardiovascular; CI, confidence interval; HR,
hazard ratio; MI, myocardial infarction.
1. Goto S, et al. Circ J. 2015;79(11):2452-2460
2. Wallentin L, et al. N Engl J Med. 2009;361:1045-57
PLATO2 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI)
CV Death, MI or Stroke 9.8 11.7
0.84
(0.77 - 0.92)
Myocardial Infarction 5.8 6.9
0.84
(0.75 - 0.95)
PHILO1 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI)
CV Death, MI or Stroke 9.0 6.3
1.47
(0.88 - 2.44)
Myocardial Infarction 6.0 3.8
1.63
(0.85 - 3.11)

13. Major + Minor Bleeding
*PLATO study bleeding criteria
CI, confidence interval; HR, hazard ratio
PLATO2 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI)
Major Bleeding 11.6 11.2
1.04
(0.95 - 1.13)
Major and Minor Bleeding 16.1 14.6
1.11
(1.03 - 1.20)
PHILO1 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI)
Major Bleeding 10.3 6.8
1.54
(0.94 - 2.53)
Major and Minor Bleeding 23.8 14.7
1.72
(1.23 - 2.40)
1. Goto S, et al. Circ J. 2015;79(11):2452-2460
2. Wallentin L, et al. N Engl J Med. 2009;361:1045-57

14. Balancing antithrombotic treatment post PCI
Intrinsic (in blue): patient’s characteristics,
clinical presentation & comorbidities) and
extrinsic
(in yellow: co-medication & procedural
aspects) variables influencing the choice,
dosing, and duration of antithrombotic
treatment.
DAPT
de-escalation
Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79.

15. Consensus on Switching ADP Blockers: Definitions
Type of Pharmacodynamic
Switch
Type of Drug Class Switch Potential for DDI
Oral*
Escalation
Clopidogrel to prasugrel Intraclass No
Clopidogrel to ticagrelor Interclass No
De-escalation
Prasugrel to clopidogrel Intraclass No
Ticagrelor to clopidogrel Interclass Yes
Change
Prasugrel to clopidogrel Interclass No
Ticagrelor to clopidogrel Interclass Yes
Intravenous
Bridge
Clopidogrel to cangrelor Interclass No
Prasugrel to clopidogrel Interclass No
Ticagrelor to clopidogrel Interclass No
Transition
Cangrelor to clopidogrel Interclass Yes
Cangrelor to prasugrel Interclass Yes
Cangrelor to ticagrelor Interclass No
Table 2. Modalities of Switching Between P2Y12 Receptor Inhibitors and
Potential for DDI
DDI indicates drug-drug interaction.
*Switching between oral agents may
be classified according to relationship
from the index event a defined as
acute (<24 hours), early (1–<30 days),
late (>30 days–1 year), and very late
(>1 year).
Angiolillo DJ, et al. Circulation. 2017;136(20):1955-1975.

16. Ticagrelor
(n = 9235), n (%)
Clopidogrel
(n = 9186), n (%)
Hazard ratio (95% CI) P-value
Non-CABG-related major bleeding
First 30 days on study drug 224 (2.47) 199 (2.21) 1.123 (0.928–1.360) 0.23
After 30 days on study drug 149 (2.17) 113 (1.65) 1.338 (1.048–1.708) 0.02
+ Adjusting by bleeding events in first 30 days 1.329 (1.041–1.698) 0.02
+ Adjusting by PCI in first 30 days 1.332 (1.043–1.701) 0.02
Non-procedure-related major bleeding
First 30 days on study drug 112 (1.25) 93 (1.05) 1.201 (0.912–1.581) 0.19
After 30 days on study drug 129 (1.90) 89 (1.30) 1.471 (1.123–1.927) 0.01
+ Adjusting by bleeding events in first 30 days 1.466 (1.119–1.920) 0.01
+ Adjusting by PCI in first 30 days 1.469 (1.121–1.925) 0.01
Table 5. Landmark analyses: first 30 days on study drug vs. after 30 days on study drug
CABG, coronary artery bypass grafting; PCI, percutaneous coronary
intervention.
Background: Early vs. late events in PLATO
Becker RC, et al. Eur Heart J. 2011;32(23):2933-44;

17. Background: Real-Life Data on DAPT de-escalation
15 % 28 %
DAPT De-escalation
Clinical & socio-
economic factors
Zettler ME, et al. Am Heart J. 2017;183:62-68.

18. SCOPE: Registry data on unguided DAPT de-escalation
De Luca L, et al. EuroIntervention. 2017;13(4):459-466.

19. Evolution of recommendations on DAPT de-escalation
ESC 2018 guidelines on myocardial revascularization – First mentioning of DAPT de-escalation1:
ESC 2020 guidelines on NSTE-ACS – Expansion of DAPT de-escalation recommendation:
 Inclusion of unguided DAPT de-escalation
 Inclusion of genotyping
1. Neumann FJ. et al. European Heart Journal (2018) 00, 1–96.
2. Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79

20. Clinical variables favoring DAPT de-escalation
Two clinical approaches for DAPT de-escalation:
1) Pro-active DAPT de-escalation: Preventive de-escalation BEFORE the occurrence of adverse events (e.g.
bleeding)
2) Re-active DAPT de-escalation: Change of treatment AFTER the occurrence of adverse events (e.g.
bleeding)
Prior Major Bleeding
Anemia
Clinically Significant Bleeding on Potent P2y12 Inhibitors
High Bleeding Risk Defined by Bleeding Risk Scores
Socio-Economic Factors Favouring the Lower Costs of Clopidogrel
Side Effects on Prasugrel And Ticagrelor, Especially Dyspnea on Ticagrelor
Need for Triple Treatment Due to New Onset Atrial Fibrillation or Left Ventricular
Thrombus After Myocardial Infarction
Table 2. Variables that could be considered for favouring de-escalation of dual antiplatelet therapy.
Claassens DM, Sibbing D. J Clin Med. 2020;9(9):2983.

21. Evolving paradigms
©
D.
Capodanno
Capodanno D, Angiolillo DJ, et al. Nat Rev Cardiol. 2018;15:480-496
TASS
CAPRIE
PERFORM
CURE
CREDO
CLARITY
COMMIT
CHARISMA
TRACER
ATLAS ACS 2
COMPASS
GEMINI ACS
SOCRATES
PEGASUS
ENTRUST
STOP-DAPT 2
SMART-CHOICE
GLOBAL LEADERS
THEMIS
AUGUSTUS
1989 1996 2001 2002 2005 2006 2011 2012 2013 2015 2016 2017 2018 2019 2020
WOEST RE-DUAL
PIONEER TWILIGHT
PCI
Prior CVA
Prior MI
Stable CVD
ACS
TRA-2P
Trials of add-on antithrombotics
Trials of aspirin replacement
Trials of aspirin-free strategies
TICO

22. Dropping aspirin, why?
©
D.
Capodanno
1. Bleeding risk
Increased risk of intracranial and extracranial
bleeding, especially in combination with
other antithrombotic drugs
2. Novel drugs
The availability of new
compounds with potent
antithrombotic efficacy could
make the use of aspirin no
longer necessary
3. Risk reduction
Contemporary drugs favorably alter
the baseline individual risk of
cardiovascular events, translating
the relative benefits of aspirin into
smaller absolute effects
Capodanno D, Angiolillo DJ, et al. Nat Rev Cardiol. 2018;15:480-496

23. Effect of 1-Month DAPT Followed by Clopidogrel vs 12-Month DAPT After PCI
OPEN-LABEL, MULTICENTER, NONINFERIORITY RANDOMIZED TRIAL
1 month of DAPT
(followed by clopidogrel monotherapy)
12 months of DAPT
(aspirin and clopidogrel)
CV death, MI, stroke, definite
ST, major or minor bleeding
at 12 mo
2.4% 3.7%
Major or minor bleeding 0.4% 1.5%
1 month of DAPT followed by clopidogrel monotherapy resulted in a significantly lower rate of NACE
Hazard ratio 0.64; 95% CI 0.42-0.98; PNI<0.001; PSUP=0.04
Watanabe H, et al. JAMA. 2019;321:2414-2427
P=0.004
STOPDAPT-2
3,045
Patients undergoing
percutaneous coronary
intervention N=1,523 N=1,522
►

24. Effect of P2Y12 Inhibitor Monotherapy vs DAPT in Patients Undergoing PCI
OPEN-LABEL, MULTICENTER, NONINFERIORITY RANDOMIZED TRIAL
3 months of DAPT
(followed by clopidogrel monotherapy)
12 months of DAPT
(aspirin and clopidogrel)
All-cause death, MI,
or stroke at 12 mo
2.9% 2.5%
BARC 2 to 5 type bleeding 2.0% 3.4%
P2Y12 inhibitor monotherapy after 3 months of DAPT resulted in noninferior rates of MACCE
Difference 0.4%; 1-sided 95% CI, -∞% to 1.3%; PNI=0.007
Hahn JY, et al. JAMA. 2019;321:2428-2437
P=0.02
SMART-CHOICE
2,993
Patients undergoing
percutaneous coronary
intervention N=1,495 N=1,498
►

25. Meta-analysis
O’ Donoghue ML, et al. Circulation. 2020;142:538–545
Bleeding MACE
P2Y12 inhibitor
SAPT preferred
P2Y12 inhibitor
SAPT preferred
DAPT
preferred
DAPT
preferred
-40%

26. Recommendations Class Level
After stent implantation in patients undergoing a
strategy of DAPT, stopping aspirin after 3-6
months should be considered, depending on the
balance between the ischaemic and bleeding
risk.
IIa A
Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79
2020 ESC Guidelines for
ACS Without ST Elevation
Antiplatelet Therapy

27. Duration of DAPT
Time
1 month
3 months
6 months
12 months
DAPT
Duration
A T
A T
C P
Aspirin Clopidogrel Prasugrel Ticagrelor
Bleeding risk
12-mo DAPT
A C
A P
A T
or
or
A P A C
DAPT
>12 mo
A T
or
DAT
>12 mo
A R
R Rivaroxaban
T
A C
A
A C
LOW HIGH VERY HIGH
Ischemic risk
NSTE-ACS
Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79
C

28. Ongoing trials
Modified from Cao D, et al. Eur Heart J. 2021;42:339-351
Study name n Study population Study intervention Primary outcome(s)
OPT-BIRISK 7,700 ACS and PCI (9-12 mo of DAPT) Clopidogrel SAPT BARC 2-5 at 9 mo
SMART-CHOICE 3 5,000 Prior PCI (≥12 months) Clopidogrel SAPT MACCE at 12 mo
STOPDAPT-2 ACS 3,008 ACS and PCI Clopidogrel SAPT NACE at 12 and 60 mo
NEOMINDSET 3,400 ACS and PCI
Prasugrel or Ticagrelor
SAPT
MACCE at 12 mo
BARC 2-5 at 12 mo
A-CLOSE 3,200 PCI (12 mo of DAPT) Clopidogrel SAPT
NACE
between 12 and 36 mo
IVUS-ACS and
ULTIMATE-DAPT
3,486 ACS and PCI Ticagrelor SAPT
BARC 2-5 and MACCE
between 1 and 12 mo
SMART-CHOICE II 1,520 PCI (12 mo of DAPT)
Clopidogrel or low-dose
ticagrelor SAPT
MACCE
between 12 and 36 mo
HOST-EXAM 5,530 PCI (12±6 mo of DAPT) Clopidogrel SAPT NACE at 24 mo

29. Summary
• ACS Day 1  potent antiplatelet is not always better in :
• For elder (age＞75) patients, high potency DAPT may result in higher bleeding rate without definite clinical benefit
• For East Asian patients, several studies focusing on the population favored the use of clopidogrel
• ACS Month 1  DAPT de-escalation (guided or unguided) is considered as an optional treatment regimen especially for ACS
patients deemed unsuitable for potent DAPT
• DAPT de-escalation is common practice after ACS-PCI (STEMI & NSTE-ACS) and can be utilized in a pro- or re-active manner
• Triggers are bleeding events/presumed high bleeding risk, drug compliance, side-effects of ticagrelor/prasugrel as well as
socio-economic aspects
• Recent ESC guidelines have included respective IIb recommendations (case-by-case decision)
• Up to Year 1  Single antiplatelet therapy
• The evidence supporting the aspirin-free strategy up to 1 year after PCI is accumulating in parallel with pharmacodynamic
studies suggesting that there is little apparent pharmacodynamic benefit in adding aspirin to a potent P2Y12 inhibitor.
• This strategy should not be intended to replace evidence-based strategies of intensified antithrombotic therapy for patients
at high thrombotic risk and low bleeding risk.